Proliferation of the BALB/MK keratinocyte cell line is exquisitely dependent on the complementary action of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-1). While confluent monolayers synthesize DNA in response to added EGF, sparse cultures that minimize autocrine stimulation have an absolute requirement for both growth factors. A newly defined growth factor isolated in our group, keratinocyte growth factor (KGF), substitutes fully for the EGF requirement indicating that these two growth factors share a common major signal transduction pathway. EGF and IGF-1 are required at distinct points in the cell cycle. EGF drives cells from the quiescent state to a point in mid-Gl. after which it is no longer required. TGF-1, on the other hand, acts after this point to stimulate progression to S-phase. These results indicate that EGF and IGF-1 are not directly interacting, but regulate separate signal transduction events. Synthesis of the CDC-2 histone Hl kinase in quiescent cells is stimulated by triggering with EGF and IGF-1. Ongoing work on CDC-2 will include analysis of growth factor requirements for activation of its kinase activity and subsequent mitotic initiation.